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1.
Cancer Res ; 82(9): 1689-1691, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35502546

RESUMO

Among the relatively few established human prostate cancer cell lines, LNCaP cells are unique in their ability to model key stages of prostate cancer progression. Analyses of LNCaP cells and their derivatives have been invaluable for elucidating important translational aspects of prostate tumorigenesis, metastasis, and drug response, particularly in the context of androgen receptor signaling. Here, we present major highlights from a wealth of literature that has exploited LNCaP cells and their derivatives to inform on prostate cancer progression and androgen response for improving the treatment of patients with prostate cancer. See related article by Horoszewicz and colleagues, Cancer Res 1983;43:1809-18.


Assuntos
Próstata , Neoplasias da Próstata , Androgênios , Linhagem Celular , Transformação Celular Neoplásica , Humanos , Masculino , Próstata/patologia , Neoplasias da Próstata/patologia
2.
PLoS One ; 17(5): e0267442, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35511909

RESUMO

Rice is critical to global food security which demands immediate attention to meet the ever-growing population. Development of improved variety is the major focus area of research, in which doubled haploid (DH) technology plays a vital role. Since, androgenesis shows its potential in DH production, this method was not capitalized specially in indica rice due to due to its recalcitrant nature to tissue culture. Success of androgenesis is governed by many important factors such as stage of anther, pre-treatment conditions, accurate concentrations of media, and plant growth regulators. Though reports of androgenesis are abundant in rice, most of them either used japonica or a specific cultivar of indica rice ecotypes. In this study, a media combination was established which is successful in producing doubled haploids from F1s of Savitri x Pokkali, IR20 x Mahulata along with the popular indica hybrids of Arize 8433DT, Arize 6453, Arize Bold, and Swift Gold. Out of 12 different media combinations tested, and 5 different durations of cold-treatments studied, N6 media with 2,4-D (2.0 mg/l) and BAP (0.5 mg/l) with 7th day cold pre-treatment was found to be most effective in all of the F1s for callus induction. Among all the F1s, rice hybrid, Arize 8433DT showed highest of 52% callus induction. In case of green shoot regeneration, MS media with NAA (0.5 mg/l), BAP (2.0 mg/l) and Kn (1.0 mg/l) (MS+C4) was found to be the most efficient of six treatments studied with highest of 58.25% regeneration in Arize 8433DT. Further, MS+C4 in combination with proline (5.0 mg/l) increased the regeneration rate to 85.99%. Besides, MS media with NAA (1.0 mg/l), Kn (0.1 mg/l) and 50 g/l sucrose was found to be most efficient for supporting root induction in all F1s. This study claims the establishment of genotype independent androgenic protocol for indica rice which could be capitalized in indica rice improvement.


Assuntos
Oryza , Androgênios , Meios de Cultura , Haploidia , Reguladores de Crescimento de Plantas/farmacologia
3.
Commun Biol ; 5(1): 416, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35508713

RESUMO

The presence of ERG gene fusion; from developing prostatic intraepithelial neoplasia (PIN) lesions to hormone resistant high grade prostate cancer (PCa) dictates disease progression, altered androgen metabolism, proliferation and metastasis1-3. ERG driven transcriptional landscape may provide pro-tumorigenic cues in overcoming various strains like hypoxia, nutrient deprivation, inflammation and oxidative stress. However, insights on the androgen independent regulation and function of ERG during stress are limited. Here, we identify PGC1α as a coactivator of ERG fusion under various metabolic stress. Deacetylase SIRT1 is necessary for PGC1α-ERG interaction and function. We reveal that ERG drives the expression of antioxidant genes; SOD1 and TXN, benefitting PCa growth. We observe increased expression of these antioxidant genes in patients with high ERG expression correlates with poor survival. Inhibition of PGC1α-ERG axis driven transcriptional program results in apoptosis and reduction in PCa xenografts. Here we report a function of ERG under metabolic stress which warrants further studies as a therapeutic target for ERG fusion positive PCa.


Assuntos
Antioxidantes , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Neoplasias da Próstata , Androgênios , Antioxidantes/farmacologia , Fusão Gênica , Humanos , Masculino , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Neoplasias da Próstata/patologia , Estresse Fisiológico , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo
5.
J Biomed Sci ; 29(1): 29, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534851

RESUMO

BACKGROUND: Castration-resistant prostate cancer (CRPC) with sustained androgen receptor (AR) signaling remains a critical clinical challenge, despite androgen depletion therapy. The Jumonji C-containing histone lysine demethylase family 4 (KDM4) members, KDM4A‒KDM4C, serve as critical coactivators of AR to promote tumor growth in prostate cancer and are candidate therapeutic targets to overcome AR mutations/alterations-mediated resistance in CRPC. METHODS: In this study, using a structure-based approach, we identified a natural product, myricetin, able to block the demethylation of histone 3 lysine 9 trimethylation by KDM4 members and evaluated its effects on CRPC. A structure-based screening was employed to search for a natural product that inhibited KDM4B. Inhibition kinetics of myricetin was determined. The cytotoxic effect of myricetin on various prostate cancer cells was evaluated. The combined effect of myricetin with enzalutamide, a second-generation AR inhibitor toward C4-2B, a CRPC cell line, was assessed. To improve bioavailability, myricetin encapsulated by poly lactic-co-glycolic acid (PLGA), the US food and drug administration (FDA)-approved material as drug carriers, was synthesized and its antitumor activity alone or with enzalutamide was evaluated using in vivo C4-2B xenografts. RESULTS: Myricetin was identified as a potent α-ketoglutarate-type inhibitor that blocks the demethylation activity by KDM4s and significantly reduced the proliferation of both androgen-dependent (LNCaP) and androgen-independent CRPC (CWR22Rv1 and C4-2B). A synergistic cytotoxic effect toward C4-2B was detected for the combination of myricetin and enzalutamide. PLGA-myricetin, enzalutamide, and the combined treatment showed significantly greater antitumor activity than that of the control group in the C4-2B xenograft model. Tumor growth was significantly lower for the combination treatment than for enzalutamide or myricetin treatment alone. CONCLUSIONS: These results suggest that myricetin is a pan-KDM4 inhibitor and exhibited potent cell cytotoxicity toward CRPC cells. Importantly, the combination of PLGA-encapsulated myricetin with enzalutamide is potentially effective for CRPC.


Assuntos
Antineoplásicos , Produtos Biológicos , Flavonoides , Neoplasias de Próstata Resistentes à Castração , Androgênios/farmacologia , Androgênios/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Flavonoides/farmacologia , Glicolatos , Glicóis/farmacologia , Glicóis/uso terapêutico , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/farmacologia , Masculino , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores Androgênicos/uso terapêutico
6.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(1): 72-78, 2022 Jan 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-35545365

RESUMO

OBJECTIVES: The pathogenesis of androgenetic alopecia (AGA) is related to the level of androgen and its metabolic pathways. The binding of androgen and androgen receptor (AR) depends on the assistance of heat shock protein 27 (HSP27). HSP27 combined with microRNAs (miR)-1 can regulate AR levels. However, it is not clear whether HSP27 and miR-1 jointly participate in the pathogenesis of AGA. This study aims to investigate the role of AR up-regulation in the pathogenesis of AGA and underlying mechanisms. METHODS: A total of 46 male AGA patients (AGA group), who admitted to the First Affiliated Hospital of Guangzhou Medical University from September 2019 to February 2020, and 52 healthy controls admitted to the same period were enrolled in this study. Serum levels of dihydrotestosterone (DHT) and HSP27 in patients and healthy controls were measured by ELISA. Western blotting was used to detect the protein expression of HSP27 and AR in scalp tissues of patients and the healthy controls. The levels of HSP27, AR, and miR-1 were analyzed using real-time PCR. Human dermal papilla cells were transfected with HSP27 siRNA to inhibit the expression of HSP27. MiR-1 and miR-1 inhibitors were transfected simultaneously or separately into cells and then the changes in AR protein expression were detected. RESULTS: The levels of DHT and HSP27 in the AGA group were (361.4±187.7) pg/mL and (89.4±21.8) ng/mL, respectively, which were higher than those in the control group [(281.8±176.6) pg/mL and (41.2±13.7) ng/mL, both P<0.05]. However, there was no significant difference in serum HSP27 and AR levels among AGA patients with different degrees of hair loss (P>0.05). Correlation analysis showed that there was a positive correlation between HSP27 level and DHT level in the AGA patients (P<0.05). The level of HSP27 mRNA in scalp tissue was negatively correlated with that of miR-1 mRNA (P<0.05). Compared with the control group, the levels of HSP27 protein, AR protein, HSP27 mRNA, and AR mRNA in scalp tissues of AGA group were significantly increased (P<0.05). The up-regulation of HSP27 in scalp tissues of AGA patients was closely related to the increased levels of AR. However, the level of miR-1 in scalp tissues of AGA patients was significantly down-regulated, contrary to the expression of AR (P<0.05). Further in cell studies showed that inhibition of HSP27 or miR-1 expression in human dermal papilla cells could inhibit the expression of AR, and inhibition of both HSP27 and miR-1 expression was found to have an accumulative effect on AR, with statistically significant differences (all P<0.05). CONCLUSIONS: HSP27 could combine with miR-1 to up-regulate AR levels, which is closely related to the development of AGA.


Assuntos
MicroRNAs , Receptores Androgênicos , Alopecia/genética , Alopecia/metabolismo , Alopecia/patologia , Androgênios , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Masculino , MicroRNAs/genética , RNA Mensageiro , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Regulação para Cima
7.
BMC Cancer ; 22(1): 482, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35501744

RESUMO

BACKGROUND: More than 60% of oligo-recurrent prostate cancer (PCa) patients treated with metastasis-directed radiotherapy (MDRT) develop biochemical recurrence within 2 years. This recurrence rate emphasises the need for improved treatment and patient selection. In line with the treatment of primary PCa, the efficacy of MDRT may be enhanced when combined with androgen-deprivation therapy (ADT). Furthermore, the availability of PSMA PET/CT offers an excellent tool for optimal patient selection for MDRT. This phase III randomised controlled trial will investigate the role of the addition of ADT to MDRT in oligo-recurrent PCa patients selected with PSMA PET/CT to enhance oncological outcome. METHODS: Two hundred and eighty patients will be randomised in a 1:1 ratio to the standard treatment arm (MDRT alone) or the experimental arm (MDRT + 6 months ADT). Patients with biochemical recurrence after primary treatment of PCa presenting with ≤ 4 metastases will be included. The primary endpoint is the 2.5-year metastases progression-free survival (MPFS). Secondary endpoints are acute and late toxicity, quality of life, biochemical progression-free survival, overall survival, and the sensitivity of the PSMA PET/CT for detecting oligometastases at low PSA-levels. So far, between March 2020 and December 2021, one hundred patients have been included. DISCUSSION: This phase III randomised controlled trial will assess the possible benefit of the addition of 6 months ADT to MDRT on metastases progression-free survival, toxicity, QoL and survival in PCa patients with 1-4 recurrent oligometastatic lesions. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04302454 . Registered 10 March 2020.


Assuntos
Neoplasias da Próstata , Antagonistas de Androgênios/uso terapêutico , Androgênios , Doença Crônica , Ensaios Clínicos Fase III como Assunto , Humanos , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
BMC Pediatr ; 22(1): 258, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35538518

RESUMO

INTRODUCTION: Anogenital distance (AGD) is a marker of prenatal androgen exposure and a tool for assessment of differences of sex development. Data for AGD in newborns have been published, but these findings may not be applicable to Thai newborns. AIM: To provide the sex-specific ranges for AGD in Thai full-term newborns. METHODS: A cross-sectional study was conducted in term newborns in Thailand, during 2016-2018. AGD was measured from anus to anterior base of penis (AGDAP) and to perineoscrotal junction (AGDAS) in males and from anus to clitoris (AGDAC) and to posterior fourchette (AGDAF) in females. AGD ratio is defined as AGDAS divided by AGDAP in males and AGDAF divided by AGDAC in females. RESULTS: A total of 364 newborns were studied (male 51.4%). The mean AGDAS, AGDAP and AGD ratio in males were 25.20 ± 4.80, 52.60 ± 6.90 and 0.48 ± 0.08 mm, respectively. The mean AGDAF, AGDAC, and AGD ratio in females were 16.50 ± 3.90, 42.60 ± 6.20 and 0.39 ± 0.08 mm, respectively. There were significant differences between AGDAS and AGDAF, AGDAP and AGDAC, and AGD ratio between males and females (p < 0.001). The AGDAS, AGDAP, AGDAF, AGDAC were correlated with birth weight and length, but AGD ratio showed no correlation. CONCLUSION: The sex-specific ranges for AGD in Thai full-term newborns were determined. AGD ratio is a useful marker of prenatal androgen exposure since it differs between sexes, but constant between races and did not vary by body size.


Assuntos
Androgênios , Pênis , Canal Anal , Estudos Transversais , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Tailândia
9.
Mar Drugs ; 20(4)2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35447901

RESUMO

Prostate cancer is a common cause of cancer death in men. In advanced stages of prostate cancer, androgen deprivation therapy (ADT) is initiated. Despite ADT, prostate cancers invariably progress to become androgen independent. A growing body of evidence implicates iron dysmetabolism in prostate cancer progression. A bioactive peptide-rich salmon protein hydrolysate (SPH) has previously been demonstrated to modulate iron homeostatic mechanisms. In the present study, the anticancer effect of SPH and bicalutamide co-treatment on LNCaP and PC3 prostate cancer cell proliferation was investigated. Our results found that SPH potentiates the anti-proliferative effect of bicalutamide in a dose-dependent manner for both cell lines. In the presence of 160 µg/mL SPH, co-treatment with 1.0 µM bicalutamide decreased LNCaP cells' relative colony survival from 25% (1.0 µM bicalutamide monotreatment) to 2% after culturing for 12 days. For PC3 cells, the relative colony survival diminished from 52% (10.0 µM bicalutamide) to 32% at an SPH concentration of 160 µg/mL. Gene expression profiling, employing quantitative real-time PCR, revealed that the inhibitory effects were related to significant FTH1 up-regulation with a concomitant TFRC down-regulation. In conclusion, our results provide in vitro evidence that SPH potentiates the growth inhibitory effect of bicalutamide on prostate cancer cells by modulating iron homeostasis mechanisms.


Assuntos
Neoplasias da Próstata , Antagonistas de Androgênios/farmacologia , Androgênios , Anilidas/farmacologia , Animais , Linhagem Celular Tumoral , Homeostase , Humanos , Ferro , Masculino , Nitrilas/farmacologia , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Hidrolisados de Proteína , Salmão , Compostos de Tosil
10.
Cell Stem Cell ; 29(4): 495-497, 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35395183

RESUMO

Despite the surrounding controversy, quantitative sex-based differences exist in the human brain. In a recent issue of Nature, Kelava et al. shed light on the mechanisms underlying increased brain volume and neuron density in males, while highlighting the importance of human PSC-derived organoids for studying human development.


Assuntos
Androgênios , Organoides , Androgênios/farmacologia , Encéfalo , Humanos , Neurônios
11.
Nutrients ; 14(7)2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35406118

RESUMO

Prostate cancer (PC) is the second leading cause of death in men in the US. PC has a high recurrence rate, and limited therapeutic options are available to prevent disease recurrence. The tryptophan-degrading enzymes 2,3-indoleamine dioxygenase (IDO1) and tryptophan dioxygenase (TDO2) are upregulated in invasive PC. (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (ß-CBT) and its C-4 epimer α-CBT are the precursors to key flavor ingredients in tobacco leaves. Nearly 40-60% of ß- and α-CBT are purposely degraded during commercial tobacco fermentation. Earlier, ß-CBT inhibited invasion, reversed calcitonin-stimulated transepithelial resistance decrease, and induced tighter intercellular barriers in PC-3M cells. This study demonstrates the in vitro ß-CBT anti-migratory (wound-healing assay) and anti-clonogenicity (colony-formation assay) activities against five diverse human PC cell lines, including the androgen-independent PC-3, PC-3M, and DU-145, the castration-recurrent CWR-R1ca, and the androgen-dependent CWR-22rv1. Meanwhile, ß-CBT potently suppressed in vivo locoregional and distant recurrences after the primary tumor surgical excision of PC-3M-Luc cell tumor engrafted in male nude mice. ß-CBT treatments suppressed organ and bone metastasis and lacked any major toxicity over the 60-day study course. ß-CBT treatments significantly suppressed IDO1, TDO2, and their final metabolite kynurenine levels in PC-3M cells. ß-CBT treatments significantly suppressed the tumor recurrence marker PSA and kynurenine levels in treated animals' plasma. ß-CBT emerges as a promising PC recurrence suppressive lead.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase , Neoplasias da Próstata , Triptofano Oxigenase , Androgênios , Animais , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Masculino , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia , Estudos Prospectivos , Tabaco , Triptofano Oxigenase/metabolismo
12.
JAMA Netw Open ; 5(4): e225432, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35363269

RESUMO

Importance: Bone health screening is recommended for patients with prostate cancer who are initiating treatment with androgen deprivation therapy (ADT); however, bone mineral density screening rates in the US and their association with fracture prevention are unknown. Objective: To assess dual-energy x-ray absorptiometry (DXA) screening rates and their association with fracture rates among older men with prostate cancer initiating treatment with androgen deprivation therapy. Design, Setting, and Participants: This retrospective nationwide population-based cohort study used data from the Surveillance, Epidemiology, and End Results database and the Texas Cancer Registry linked with Medicare claims. Participants comprised 54 953 men 66 years or older with prostate cancer diagnosed between January 2005 and December 2015 who initiated treatment with ADT. Data were censored at last enrollment in Medicare and analyzed from January 1 to September 30, 2021. Exposures: Dual-energy x-ray absorptiometry screening within 12 months before and 6 months after the first ADT claim. Main Outcomes and Measures: Frequencies of DXA screening and fracture (any fracture and major osteoporotic fracture) and overall survival were calculated. The association between DXA screening and fracture was evaluated using a multivariable Cox proportional hazards model with propensity score adjustment. Results: Among 54 953 men (median age, 74 years; range, 66-99 years) with prostate cancer, 4689 (8.5%) were Hispanic, 6075 (11.1%) were non-Hispanic Black, 41 453 (75.4%) were non-Hispanic White, and 2736 (5.0%) were of other races and/or ethnicities (including 121 [0.2%] who were American Indian or Alaska Native; 1347 [2.5%] who were Asian, Hawaiian, or Pacific Islander; and 1268 [2.3%] who were of unknown race/ethnicity). Only 4362 men (7.9%) received DXA screening. The DXA screening rate increased from 6.8% in 2005 to 8.4% in 2015. Lower screening rates were associated with being single (odds ratio [OR], 0.89; 95% CI, 0.81-0.97; P = .01) and non-Hispanic Black (OR, 0.80; 95% CI, 0.70-0.91; P < .001), living in small urban areas (OR, 0.77; 95% CI, 0.66-0.90; P = .001) and areas with lower educational levels (OR, 0.75; 95% CI, 0.67-0.83; P < .001), and receiving nonsteroidal androgens (OR, 0.57; 95% CI, 0.39-0.84; P = .004). Overall, 9365 patients (17.5%) developed fractures after initial receipt of ADT. The median time to first fracture was 31 months (IQR, 15-56 months). In the multivariable model with propensity score adjustment, DXA screening was not associated with fracture risk at any site (hazard ratio [HR], 0.96; 95% CI, 0.89-1.04; P = .32) among men without previous fractures before receipt of ADT. However, previous DXA screening was associated with a decreased risk of major fractures (HR, 0.91; 95% CI, 0.83-1.00; P = .05) after propensity score adjustment. Conclusions and Relevance: In this study, low DXA screening rates were observed among older men with localized or regional prostate cancer after initiation of treatment with ADT. Despite low rates of screening, evaluation of bone mineral density with a DXA scan was associated with lower risk of major fractures. These findings suggest that DXA screening is important for the prevention of major fractures among older men with prostate cancer and that implementation strategies are needed to adopt bone health screening guidelines in clinical practice.


Assuntos
Osteoporose , Fraturas por Osteoporose , Neoplasias da Próstata , Idoso , Antagonistas de Androgênios/efeitos adversos , Androgênios/uso terapêutico , Densidade Óssea , Estudos de Coortes , Humanos , Masculino , Medicare , Osteoporose/diagnóstico , Osteoporose/epidemiologia , Osteoporose/etiologia , Neoplasias da Próstata/epidemiologia , Estudos Retrospectivos , Estados Unidos/epidemiologia
13.
Urol Clin North Am ; 49(2): 309-321, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35428436

RESUMO

Androgen deprivation therapy, used alone or in combination, inhibits androgen activity either upstream at the level of the pituitary gland or downstream by disrupting the androgenesis pathway in the adrenal or androgen activity in prostate cells. Its appropriate utilization varies depending on disease stage, aggressivity, and resistance. Special consideration should be given to side effects, as it can affect patients' quality of life and their treatment of other conditions.


Assuntos
Antagonistas de Androgênios , Neoplasias da Próstata , Antagonistas de Androgênios/efeitos adversos , Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Qualidade de Vida
14.
Beijing Da Xue Xue Bao Yi Xue Ban ; 54(2): 294-298, 2022 Apr 18.
Artigo em Chinês | MEDLINE | ID: mdl-35435195

RESUMO

OBJECTIVE: Androgen deficiency is common in aging males and may have unfavourable health consequences. Large-scale studies suggested low testosterone level might increse mortality and morbidity in ageing males. However, young men with low testosterone level might be neglected. Recent studies reported young men with infertility may have reduced testosterone level. To investigate the incidence of androgen deficiency in males with infertility and possible factors affecting the low testosterone level. METHODS: Between January 2011 and December 2012, 407 men with infertility caused by varicocele (VC), obstructive azoospermia (OA) and nonobstructive azoospermia (NOA) in our center were included. The number of men in each group of OA, NOA and VC was 141, 97 and 169, respectively. All the eligible patients underwent a serum testosterone assessment by a single morning blood draw (between 8:00 to noon) to test for concentration of the total testosterone. All serum samples were determined by radioimmunoassay in our andrology laboratory. Androgen deficiency was defined as having a total testosterone level less than 300 ng/dL. RESULTS: The mean age was (30.4±5.8) years. The mean testosterone level was (4.18±1.64) ng/dL (range 0.30 to 11.32 ng/dL). The overall incidence of androgen deficiency was 26.5% (108/407). The incidences of androgen deficiency in NOA, OA and VC groups were 40.2% (39/97), 19.1% (27/141) and 24.9% (42/169), respectively, which were significantly higher in the NOA than in the VC and OA groups (P < 0.001). The incidences had no difference between the VC and OA groups (P=0.229). Univariate analysis revealed the cause of infertility, FSH and the mean testis volume as possible affecting factors for androgen deficiency. However, on multivariate analysis the only cause of infertility was an independent predictor. The incidence of androgen deficiency was the highest in the NOA group [OR 0.492 (95% confidence interval 0.288-0.840)]. CONCLUSION: NOA and varicocele might be risk factors of androgen deficiency. Young men with NOA may have a higher possibility of low testosterone level. Testosterone level should be followed up after NOA and varicocele treatment. Androgen deficiency should be assessed in males with infertility in clinical practice.


Assuntos
Azoospermia , Varicocele , Adulto , Androgênios , Azoospermia/etiologia , Feminino , Humanos , Masculino , Testículo , Testosterona , Varicocele/complicações , Adulto Jovem
15.
Genes (Basel) ; 13(4)2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35456428

RESUMO

BACKGROUND: Prostate cancer represents 3.8% of cancer deaths worldwide. For most prostate cancer cells to grow, androgens need to bind to a cellular protein called the androgen receptor (AR). This study aims to demonstrate the expression of five microRNAs (miRs) and its influence on the AR formation in patients from the northern region of Brazil. MATERIAL AND METHODS: Eighty-four tissue samples were investigated, including nodular prostatic hyperplasia (NPH) and acinar prostatic adenocarcinoma (CaP). Five miRs (27a-3p, 124, 130a, 488-3p, and 506) were quantified using the TaqMan® Real Time PCR method and AR was measured using Western blotting. RESULTS: Levels of miRs 124, 130a, 488-3p, and 506 were higher in NPH samples. Conversely, in the CaP cases, higher levels of miR 27a-3p and AR were observed. CONCLUSION: In the future, these microRNAs may be tested as markers of CaP at the serum level. The relative expression of AR was 20% higher in patients with prostate cancer, which suggests its potential as a biomarker for prostate malignancy.


Assuntos
Adenocarcinoma , MicroRNAs , Neoplasias da Próstata , Adenocarcinoma/genética , Androgênios , Linhagem Celular Tumoral , Humanos , Masculino , MicroRNAs/metabolismo , Próstata/patologia , Neoplasias da Próstata/patologia
16.
Lancet ; 399(10336): 1695-1707, 2022 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-35405085

RESUMO

BACKGROUND: Current standard of care for metastatic castration-sensitive prostate cancer supplements androgen deprivation therapy with either docetaxel, second-generation hormonal therapy, or radiotherapy. We aimed to evaluate the efficacy and safety of abiraterone plus prednisone, with or without radiotherapy, in addition to standard of care. METHODS: We conducted an open-label, randomised, phase 3 study with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Belgium, France, Ireland, Italy, Romania, Spain, and Switzerland. Eligible patients were male, aged 18 years or older, with histologically confirmed or cytologically confirmed de novo metastatic prostate adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0-1 (or 2 due to bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen deprivation therapy alone or with intravenous docetaxel 75 mg/m2 once every 3 weeks), standard of care plus radiotherapy, standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), or standard of care plus radiotherapy plus abiraterone. Neither the investigators nor the patients were masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival. Abiraterone efficacy was first assessed in the overall population and then in the population who received androgen deprivation therapy with docetaxel as standard of care (population of interest). This study is ongoing and is registered with ClinicalTrials.gov, NCT01957436. FINDINGS: Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled (one patient subsequently withdrew consent for analysis of his data) and assigned to receive standard of care (n=296), standard of care plus radiotherapy (n=293), standard of care plus abiraterone (n=292), or standard of care plus radiotherapy plus abiraterone (n=291). Median follow-up was 3·5 years (IQR 2·8-4·6) for radiographic progression-free survival and 4·4 years (3·5-5·4) for overall survival. Adjusted Cox regression modelling revealed no interaction between abiraterone and radiotherapy, enabling the pooled analysis of abiraterone efficacy. In the overall population, patients assigned to receive abiraterone (n=583) had longer radiographic progression-free survival (hazard ratio [HR] 0·54, 99·9% CI 0·41-0·71; p<0·0001) and overall survival (0·82, 95·1% CI 0·69-0·98; p=0·030) than patients who did not receive abiraterone (n=589). In the androgen deprivation therapy with docetaxel population (n=355 in both with abiraterone and without abiraterone groups), the HRs were consistent (radiographic progression-free survival 0·50, 99·9% CI 0·34-0·71; p<0·0001; overall survival 0·75, 95·1% CI 0·59-0·95; p=0·017). In the androgen deprivation therapy with docetaxel population, grade 3 or worse adverse events occurred in 217 (63%) of 347 patients who received abiraterone and 181 (52%) of 350 who did not; hypertension had the largest difference in occurrence (76 [22%] patients and 45 [13%], respectively). Addition of abiraterone to androgen deprivation therapy plus docetaxel did not increase the rates of neutropenia, febrile neutropenia, fatigue, or neuropathy compared with androgen deprivation therapy plus docetaxel alone. INTERPRETATION: Combining androgen deprivation therapy, docetaxel, and abiraterone in de novo metastatic castration-sensitive prostate cancer improved overall survival and radiographic progression-free survival with a modest increase in toxicity, mostly hypertension. This triplet therapy could become a standard of care for these patients. FUNDING: Janssen-Cilag, Ipsen, Sanofi, and the French Government.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Próstata , Antagonistas de Androgênios , Androgênios , Androstenos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Castração , Docetaxel/uso terapêutico , Feminino , Humanos , Hipertensão/etiologia , Masculino , Prednisona/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia
17.
Technol Cancer Res Treat ; 21: 15330338221080941, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35379053

RESUMO

Background: The androgen receptor (AR) has recently emerged as a useful marker for the more favorable prognosis and better outcomes among women with estrogen receptor (ER) + ve breast cancer (BC) and the further refinement of BC subtype. Furthermore, AR expression in ER - ve tumors has a particular prognostic significance. Additionally, the ratio of nuclear AR to ER may critically have an influence on tumor biology and respond to endocrine therapy. Purpose: To define the AR expression and AR:ER ratio, and explored their correlation with the clinicopathological features, prognosis, and survival outcomes in the various subclasses of invasive BC. Methods: The current study was conducted on 522 BC patients who had surgical operations, without neoadjuvant chemotherapy by applying a retrospective cohort analysis. The clinicopathological characteristics were recorded. Immunohistochemical staining was performed on AR, ER, PR, HER2, and Ki67. Expression of AR was paired into different immunophenotypes for analysis with clinicopathological features and survival. All BC patients' survival was analyzed using Kaplan-Meier and log-rank models. Results: The presence of AR was detected in 65.3%. Positive AR, the ratio of AR:ER<2, luminal androgen receptor (LAR) + and AR + HER2 + immunophenotypes were significantly associated with better prognostic features. AR:ER<2 was observed in the prolonged overall survival (OS) and disease-free survival (DFS) (87.9 and 86.2%, respectively) compared to AR:ER≥2 (25.0% in both) (P < .001). In contrast, in HR + ve BCs, the AR expression was not significantly correlated with survival. The multivariate model revealed that the ratio of nuclear AR to ER remained as an independent prognostic variable. Conclusion: The AR expression had a distinct OS and DFS. The AR:ER ratio is an independent indicator for predicting the OS and DFS of BC patients in both univariate and multivariate analyses.


Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Androgênios , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Humanos , Receptores Androgênicos/genética , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Estudos Retrospectivos , Vietnã
18.
Sci Rep ; 12(1): 6094, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35413990

RESUMO

Androgen and androgen receptor (AR) targeted therapies are the main treatment for most prostate cancer (PC) patients. Although AR signaling inhibitors are effective, tumors can evade this treatment by transforming to an AR-negative PC via lineage plasticity. OCT1 is a transcription factor interacting with the AR to enhance signaling pathways involved in PC progression, but its role in the emergence of the AR-negative PC is unknown. We performed chromatin immunoprecipitation sequencing (ChIP-seq) in patient-derived castration-resistant AR-negative PC cells to identify genes that are regulated by OCT1. Interestingly, a group of genes associated with neural precursor cell proliferation was significantly enriched. Then, we focused on neural genes STNB1 and PFN2 as OCT1-targets among them. Immunohistochemistry revealed that both STNB1 and PFN2 are highly expressed in human AR-negative PC tissues. Knockdown of SNTB1 and PFN2 by siRNAs significantly inhibited migration of AR-negative PC cells. Notably, knockdown of PFN2 showed a marked inhibitory effect on tumor growth in vivo. Thus, we identified OCT1-target genes in AR-negative PC using a patient-derived model, clinicopathologial analysis and an animal model.


Assuntos
Neoplasias da Próstata , Receptores Androgênicos , Androgênios/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Fator 1 de Transcrição de Octâmero , Profilinas/genética , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais
19.
Lancet Oncol ; 23(5): 671-681, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35427469

RESUMO

BACKGROUND: The optimal duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains controversial. The DART 01/05 trial was designed to determine whether long-term androgen deprivation is superior to short-term androgen deprivation when combined with high-dose radiotherapy. The 5-year results showed that 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy significantly improved biochemical control, metastasis, and overall survival, especially in patients with high-risk disease. In this report, we present the 10-year final results of the trial. METHODS: This open-label, phase 3, randomised, controlled trial was done in ten hospitals in Spain. The eligibility criteria included patients aged 18 years or older with histologically confirmed T1c to T3, N0, and M0 adenocarcinoma of the prostate, according to the 2002 classification of the American Joint Committee on Cancer, with intermediate-risk and high-risk factors, prostate-specific antigen (PSA) less than 100 ng/mL, and a Karnofsky performance score of at least 70%. Patients were randomly assigned (1:1) to receive 4 months of neoadjuvant and concomitant short-term androgen deprivation (STAD) plus high-dose radiotherapy (minimum dose 76 Gy; median dose 78 Gy) or to receive the same treatment followed by 24 months of adjuvant long-term androgen deprivation (LTAD), via a randomisation scheduled generated by Statistical Analysis Software programme (version 9.1) and an interactive web response system. Patients assigned to the STAD group received 4 months of neoadjuvant and concomitant androgen deprivation (oral flutamide 750 mg per day or oral bicalutamide 50 mg per day) with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy was added during the first 2 months of treatment. Patients assigned to LTAD continued with goserelin every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival at 5 years. For this 10-year study we analysed overall survival, metastasis-free survival, biochemical disease-free survival, and cause-specific survival. Analysis was by intention to treat. This trial is closed and is registered at ClinicalTrials.gov (NCT02175212) and in the EU Clinical Trials Register (EudraCT 2005-000417-36). FINDINGS: Between Nov 7, 2005, and Dec 20, 2010, 355 patients were enrolled. One patient in the STAD group withdrew from the trial, hence 354 participants were randomly assigned to STAD (n=177) or LTAD (n=177). The median follow-up was 119·4 months (IQR 100·6-124·3). The 10-year biochemical disease-free survival for LTAD was 70·2% (95% CI 63·1-77·3) and for STAD was 62·3% (54·9-69·7; hazard ratio [HR] 0·84; 95% CI 0·50-1·43; p=0·52). At 10 years, overall survival was 78·4% (72·1-84·8) for LTAD and 73·3% (66·6-80·0) for STAD (HR 0·84; 95% CI 0·55-1·27; p=0·40), and metastasis-free survival was 76·0% (69·4-82·7) for LTAD and 70·9% (64·0-77·8) for STAD (HR 0·90; 95% CI, 0·37-2·19; p=0·81). For the subgroup of high-risk patients, the 10-year biochemical disease-free survival was 67·2% (57·2-77·2) for LTAD and 53·7% (43·3-64·1) for STAD (HR 0·90; 95% CI 0·49-1·64; p=0·73), the 10-year overall survival was 78·5% (69·6-87·3) for LTAD and 67·0% (57·3-76·7) for STAD (HR 0·58; 95% CI 0·33-1·01; p=0·054), and the 10-year metastasis-free survival was 76·6% (95% CI 67·6-85·6) for LTAD and 65·0% (55·1-74·8) for STAD (HR 0·89; 95% CI 0·33-2·43; p=0·82). Only 11 (3%) of 354 patients died from prostate cancer, all of them in the high-risk subgroup (five in the LTAD group and six in the STAD group). 76 (21%) patients died from other causes (mainly second malignancies in 31 [9%] and cardiovascular disease in 21 [6%]). No treatment-related deaths were observed. INTERPRETATION: After an extended 10-year follow-up, we were unable to support the significant benefit of LTAD reported at 5 years. However, the magnitude of the benefit was clinically relevant in high-risk patients. Intermediate-risk patients treated with high-dose radiotherapy do not benefit from LTAD. A biological characterisation with the inclusion of genomic testing is needed in the decision-making process. FUNDING: Grupo de Investigación en Oncología Radioterápica and Sociedad Española de Oncología Radioterápica, the National Health Investigation Fund, and AstraZeneca.


Assuntos
Neoplasias da Próstata , Antagonistas de Androgênios/efeitos adversos , Androgênios , Gosserrelina , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia
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